tbuckley/cabot-search huggingface dataset:
EOLP-03. BALANCING HOPE AND REALITY: A THEMATIC ANALYSIS OF PATIENT-CLINICIAN COMMUNICATIONS AT INITIAL NEURO-ONCOLOGY OUTPATIENT CLINIC VISITS FOR PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA
Authors: Anna Hauswirth, Sumita Strander, Jennifer Temel, Lara Traeger, Deborah Forst
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND: Patients facing a new diagnosis of a high-grade glioma often report an inaccurate understanding of their poor prognosis. However, how oncologists communicate prognostic information at initial visits in the neuro-oncology clinic has not been fully studied. We sought to analyze how physicians share this devastating news with patients and their caregivers. METHODS: We audio-recorded and transcribed the initial neuro-oncology clinic appointments with patients with high-grade gliomas at a single academic medical center; during these visits, neuro-oncology clinicians (physicians and fellowship trainees) shared diagnostic and prognostic information with patients and caregivers. We analyzed visit content using thematic analysis. RESULTS: We enrolled 14 patients with newly diagnosed malignant gliomas (glioblastoma: 11 and anaplastic astrocytoma: 3); 9 neuro-oncology clinicians (6 attending physicians and 3 fellowship trainees) participated in the appointments. Emergent themes included: (1) Neuro-oncologists proactively offered diagnostic and prognostic information using clear and simple language to disclose incurability (e.g., that this is an “incurable,” “aggressive” cancer that “will come back”); (2) Neuro-oncologists shifted their language, content, and tone to balance this bad news with clinical information that offered hope and optimism (e.g., emphasizing a patient’s positive prognostic indicators, sharing examples of long-term survivors, and discussing ongoing research and clinical trials); (3) Neuro-oncologists further balanced diagnostic disclosure with offers of logistical support (e.g., support programs for the patient’s minor children and access to 24/7 telephone care) and emotional support (e.g., stating "I am always here”) to patients and family members. CONCLUSION: During initial clinic visits with patients with high-grade gliomas, neuro-oncologists disclosed frank information about the incurability of the illness while balancing this life-changing news with statements of hope, optimism, and support. Understanding how clinicians provide diagnostic and prognostic information may help inform efforts to improve patient-clinician communication and optimize support for patients and their families.
EPCO-24. DNA METHYLATION-BASED SUBCLASS PREDICTS THE EFFECT OF THE EXTENT OF RESECTION ON SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Luuk Dankmeijer, Lucas Westerink, Pieter Wesseling, Philip de Witt Hamer, Mathilde Kouwenhoven, Evert-Jan Kooi, Niels Verburg
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND DNA methylation-based classification of diffuse glioma is increasingly used in daily practice. Yet, little is known regarding the prognostic and predictive value of DNA methylation-based subclasses of IDH-wildtype glioblastoma. A recent study found a predictive value for the effect of extent or resection (EOR) on survival for DNA methylation-based subclasses using the v11.4 classifier. We set out to validate these findings in an independent cohort and to test if these results are similar using a more recent version (v12.5) of the classifier. METHODS This concerns a single-center retrospective cohort study of all patients with a glioblastoma, IDH-wildtype of whom DNA methylation was obtained. Patient and tumor characteristics, pre-operative Karnofsky performance status and EOR (complete, subtotal, partial, biopsy) were retrieved. DNA methylation-based classification and MGMT-promoter status were obtained using version 11.4 and 12.5 of the Heidelberg classifier. Progression-free survival (PFS) and overall survival (OS) were collected and validated using the national brain tumor registry. RESULTS Of 149 patients, the subtype was Mesenchymal in 57 (38%), RTK1 in 41 (28%), and RTK2 in 51 patients (34%). PFS and OS did not differ between the three subclasses, also not after pooling RTK1 and RTK2 into one Classical subclass. Complete or subtotal resection resulted in a longer OS than partial resection or biopsy in the entire cohort. This was similar for the pooled Classical subclass. In the Mesenchymal subclass, however, there was no survival advantage for complete or subtotal resection over partial resection or biopsy. These results were similar with the 11.4 and 12.5 classifier version. CONCLUSION In IDH-wildtype glioblastoma of the Mesenchymal subclass complete or subtotal resection does not result in a survival benefit. Our findings evoke the need for pre- or intraoperative assessment of the DNA-methylation based subclass of IDH-wildtype glioblastoma.
DDDR-27. CLASS I HDAC INHIBITOR AGAINST TM-MEDIATED NETWORK CONNECTIVITY IN GLIOBLASTOMA
Authors: Sophie Weil, Daniel Domínguez Azorín, Dirk Hoffmann, Sandra Horschitz, Ammar Jabali, Erik Jung, Philipp Koch, Wolfgang Wick, Frank Winkler
Journal: Neuro-Oncology (2023)

Abstract Tumor microtubes (TMs) are long thin cellular protrusions extended by one glioblastoma cell to connect to another and integrate into a communicating network that contributes to glioblastoma’s high therapy resistance. Understanding the biological functions of tumor cell connectivity and overcoming network resistance has emerged as a new therapeutic opportunity. The combinatorial treatment of an anti-TM compound with a cytotoxic treatment has come to focus after it was shown that non-connected glioblastoma cells are more vulnerable to cytotoxic therapy. Besides the development of therapies against specific proteins in TM function, other drugs have also been repurposed and tested for their anti-TM activity and potential additional benefits with radiotherapy. Among these, we tested histone deacetylase (HDAC) inhibitors regarding their potential to overcome TM mediated connectivity and thereby open vulnerabilities in glioblastoma. To investigate the drugs, we applied our drug testing pipeline in vitro and in vivo. Here, we observed fewer TMs in an in vitro monolayer of glioblastoma monoculture after treatment with a class I HDAC inhibitor as opposed to two other compounds from the HDAC inhibitor group. In a 3D co-culture model with human neuronal organoids, treatment with the most promising class I HDAC inhibitor showed a dose-dependent inhibitory effect on cell proliferation and TMs. We then continued to examine the HDAC inhibitor’s effect in our in vivo two photon microscopy model with radiotherapy as cytotoxic co-treatment. After the implantation and establishment of xenograft glioblastoma under a chronic cranial window in mice, treatment with the HDAC inhibitor was started and a course of radiotherapy was added. After six weeks after treatment start, tumors of the co-treated animals were smaller than in animals that were only irradiated. Further studies will involve the examination of the underlying biological mechanism of the anti-TM effects and continued long-term treatment to further improve overall anti-tumor effectivity.
BIOM-65. NEW BIOMARKERS FOR THE DIAGNOSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA IN CEREBROSPINAL FLUID: AN EXPLORATORY MULTICENTER RETROSPECTIVE COHORT STUDY
Authors: Josephus van Rooij, Peter Wessels, Eveline Delemarre, Bob Meek, Henk Ruven, Tatjana Seute, Monique Minnema, Stefan Nierkens, Tom Snijders
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma which may be treated with curative intent. Diagnosis often requires a brain biopsy, which is associated with complications and delay of diagnosis. Cerebrospinal fluid (CSF) analysis can currently provide a diagnosis (without the need for a biopsy) in only a minority of PCNSL patients. The aim of this study is to identify new potential biomarkers in CSF for patients with clinical suspicion of PCNSL, to improve the diagnostic yield of CSF analysis. METHODS CSF samples were analyzed from a retrospective cohort that included patients with clinical suspicion of PCNSL at two Dutch hospitals between August 2020 and October 2021. First-step analysis consisted of targeted multiplex biomarker analysis using a proximity extension assay (Olink), allowing the simultaneous analysis (relative expression levels) of 184 protein markers in a small CSF volume. To validate the discovered biomarkers in a quantitative manner, a second analysis was performed in a subgroup of patients with a bead-based multiplex immune-assay (Luminex). RESULTS A total of 76 patients were included, of whom 11 patients (14%) were diagnosed with PCNSL. The mean age was 62 years (range 22-83 years), and 62% of the patients were male. In the primary analysis, 31 markers showed significant differences (p&amp;lt; 0.05) between PCNSL patients and controls. After correction for multiple testing, 6 markers remained significant, including the known chemokine marker CXCL13, as well as new markers. The quantitative analysis confirmed significant differences (p&amp;lt; 0.05) for 3 markers: CXCL10, programmed cell death protein 1 (PDCD1) and FAS natural ligand (FASLG). CONCLUSION We identified a novel panel of potential diagnostic markers in CSF for the diagnosis of PCNSL. The diagnostic value of these markers will be validated in an ongoing multicenter prospective study.
QOL-10. MULTIDISCIPLINARY MEDICAL CARE SYSTEM FOR BRAIN TUMOR SURVIVORS IN JAPAN
Authors: Norihiko Saito, Nozomi Hirai, Yuki Koyahara, Sho Sato, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Hideaki Izukura, Takatoshi Sakurai, Satoshi Iwabuchi
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: Brain tumor patients suffer from psychological distress and various aftereffects. Although the number of "brain tumor survivors" has been increasing due to improved outcomes of brain tumor treatment, the support system for them is inadequate in Japan. Therefore, we are examining issues affecting the QOL faced by brain tumor patients and their families, with the aim of establishing a fulfilling medical care system with a multidisciplinary approach. Here, we report on the current status of the multidisciplinary medical care system. METHODS: The EORTC QLQ-C30, 14-item resilience scale, PHQ-9, and Pittsburgh Sleep Quality Index are used to assess QOL. Based on these, an optimal care plan for brain tumor patients was developed through multidisciplinary team of professionals among physicians, nurses, clinical neuropsychologists, speech-language pathologists, occupational therapists, pharmacists, and nutritionists. A brain tumor survivorship program designed to support brain tumor patients, survivors, and care givers was developed, and this program was launched in December 2021. RESULTS AND DISCUSSION: Quality of life assessment of brain tumor patients revealed their problems and unmet needs, which enabled the development of optimal care plans in collaboration with multiple disciplines. In addition, neuropsychological approaches and cognitive behavioral therapy have been utilized as interventions for cognitive dysfunction. The Brain Tumor Survivorship Program has 18 participants as of May 31, 2023. In addition to providing online resources, patient support meetings were held virtually, providing an opportunity for participants to communicate directly with each other. CONCLUSION: We believe it is essential to establish a long-term follow-up system specifically for brain tumor patients. Through the multidisciplinary medical care system, we plan to continue to scientifically investigate and develop a support system for the various survivorship issues that brain tumor patients and their families experience across the trajectory of the illness.
RADT-37. INTERIM RESULTS OF ACCELERATOR-BASED BORON NEUTRON CAPTURE THERAPY, RANDOMIZED CONTROLLED TRIAL FOR RECURRENT AND REFRACTORY HIGH-GRADE MENINGIOMAS
Authors: Shin-Ichi Miyatake, Masahiko Wanibuchi, Shinji Kawabata, Motomasa Furuse, Naosuke Nonoguchi, Keiji Nihei, Naonori Fu, Koji Ono
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND High-grade meningiomas (HGMs) recurred after X-ray treatment showed 5.2 months as median progression free survival (mPFS) and only 24.6 months as median overall survival (mOS) from the literatures. Recently, we showed much more excellent OS and PFS using reactor-based boron neutron capture therapy (BNCT) (Neuro-Oncology 24:90-98, 2022). Based on these data, we started “A phase II investigator-lead RCT using accelerator-based BNCT system for refractory recurrent high-grade meningioma”, with the aid of Japanese governmental financial support. METHODS We prepared 2 study arms, BNCT test treatment arm (12 subjects) and control best supportive care arm (6 subjects) in RCT fashion. PFS judged by third party committee was set-up as primary endpoint and PFS judged by investigators themselves and OS of BNCT arm were set-up as secondary endpoints. To diminish ethical problems of this RCT, rescue BNCT is permitted for control group patients, if they showed progress disease during the observation period. Macdonald criteria was adopted for assessment. The first patient-in was August 2019 and the last patient-in was August 2021. Interim results of this trial: Three and two grade 3 subjects were included in BNCT and control arm, respectively. Others were grade 2 subjects. As of April 20, 2023, mPFS judged by investigators showed 90 weeks and 8 weeks for BNCT and control arm, respectively (P = 0.0004). OS-2 year rates of BNCT and control arms are 91.7% and 25%, respectively (p = 0.01) CONCLUSION Primary endpoint, mPFS judged by third party committee is still being closed and unknown, so far, until the end of the trial (August 2024). With regard to secondary endpoints, there are marked differences in both arms in mPFS judged by investigators. Also, OS in BNCT arm is extremely excellent in comparison with EORTC RCT of “trabectedine” and PD-1 blockade reports, just recently appeared.
EXTH-48. PROTOPORPHYRIN IX LEVELS IN PATIENTS’ PLASMA, BLOOD, AND BRAIN TUMOR BY A VALIDATED LC-MS/MS METHOD
Authors: William Knight, Tigran Margaryan, Nader Sanai, Artak Tovmasyan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Protoporphyrin IX (PPIX) is an intermediate molecule in the heme biosynthesis pathway. Cancer cells, having a higher metabolic rate than normal cells, accumulate PPIX when an exogenous dose of its precursor, 5-aminolevulinic acid (5-ALA), is administered. 5-ALA is currently approved by the U.S. FDA for the visualization of high-grade gliomas (HGG) and fluorescence guided surgery. 5-ALA and PPIX are also central to experimental treatments of photodynamic and sonodynamic therapy for HGG patients. Accurate quantitation of PPIX in brain tumor, plasma, and blood is necessary to evaluate its pharmacokinetics and hence optimize its therapeutic benefit in the context of experimental therapies and tumor visualization. METHODS Plasma was used as a matrix for PPIX quantitation in plasma and brain homogenate. Brain homogenates (1:7) were prepared in 5 mM ammonium formate containing 0.2% formic acid. A separate plasma curve was used for blood quantitation. Before protein precipitation, blood and corresponding calibrators were diluted five times with water. PPIX was extracted from human plasma, blood, and brain homogenate samples using methanol containing PPIX-d6 (internal standard). Sample preparation was performed under low light conditions (&amp;lt; 5 lux). Chromatographic separation of the analyte was achieved isocratically on Phenomenex Kinetex™ EVO C18 column, with a total run time of 3.5 min. Analyte detection was performed on Sciex QTRAP 6500+ MS/MS detector. RESULTS The method was validated for 1-2000 nmol/L range. Using plasma as a surrogate matrix, the maximum coefficient of variation for intra- and inter-day precision and accuracy were within acceptable ranges for all matrices. CONCLUSIONS A new rapid and sensitive LC-MS/MS method was successfully validated for the PPIX quantitation in human plasma, blood, and brain. It is currently used in a sonodynamic therapy clinical trial (NCT04559685) to evaluate PPIX pharmacokinetic profile in plasma and blood, and to determine levels in brain tumors of HGG patients.
BIOM-39. GENETIC VARIANTS ASSOCIATED WITH DISTANT RECURRENCE IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD THERAPY
Authors: Vincent Fougner, Shivani Chiranth, Christina Yde, Dorte Nørøxe, Ib Christensen, Benedikte Hasselbalch, Ulrik Lassen, Hans Poulsen, Thomas Urup
Journal: Neuro-Oncology (2023)

Abstract Infiltrative growth is a hallmark of glioblastoma and is a major factor in therapeutic failure. Genetic variants predictive of distant recurrence may serve as novel treatment targets. The aim is to identify genetic variants associated with distance recurrence in glioblastoma patients. METHODS: From a prospective cohort of consecutive, non-selected glioblastoma patients administered standard therapy between 2016-2021 at Rigshospitalet, all patients with a genomic tumor profile were included. Distant recurrence was defined as a new contrast-enhancing tumor &amp;gt; 2 cm from the initial lesion. Tumor tissue was analyzed by RNA- and DNA-sequencing (WES or WGS). Genetic variants were defined as pathogenic and likely-pathogenic variants based on genomic reports. Predefined candidate biomarkers included: i) the most common genetic variants in the cohort (mutational frequency &amp;gt; 2%), ii) the number of reported variants per sample, and iii) groups of genetic variants according to the common signaling pathways. Candidates were screened for association with time to distant recurrence using univariate Cox regression analysis. Biomarkers with p &amp;lt; 0.20 were considered for multivariate analysis adjusted for known prognostic factors with death as the competing risk. RESULTS: A total of 236 patients were included, and 208 patients (88%) were evaluable for recurrence pattern. Distant recurrence was observed in 40 patients (19%). Patients with distant and local recurrence showed no difference in progression-free survival (p = 0.58), while distant recurrence tended to have a poor overall survival (OS, p = 0.09). The OS from time of first recurrence was significantly poorer for patients with distant recurrence compared to local recurrence (p = 0.01) with a median OS of 7.2 months (95%CI: 5.9-8.5) and 10.9 months (95%CI: 9.8-12). The median frequency of called gene variants was 4 (range 0-11) per sample. CONCLUSION: Patients with distant recurrence have a poor prognosis. Final analyses will be presented.
IMMU-17. INDUCING IMMUNE RESPONSE WITH FLASH AND CONVENTIONAL DOSE-RATE RADIATION IN DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Robyn Gartrell, Hanna Minns, Oscar Padilla, Hong-Jian Wei, Andrea Webster-Carrion, Masih Tazhibi, Nicholas McQuillan, Xu Zhang, Matthew Gallitto, Rebecca Yeh, Zhiguo Zhang, Luca Szalontay, Jovana Pavisic, Guy Garty, James Garvin, Peter Canoll, Claire Vanpouille-Box, Vilas Menon, Marta Olah, Raul Rabadan, Cheng-Chia Wu
Journal: Neuro-Oncology (2023)

Abstract Diffuse Midline Glioma is a universally fatal inoperable pediatric brain tumor associated with H3K27M mutation and median survival of 9-15 months. Radiation therapy (RT) is the primary treatment, extending life by only three months. Conventional dose-rate RT (2Gy/min, CONV) can induce an immune response with type 1 interferon (IFN1) in multiple cancers including adult brain tumors. Ultra-fast dose-rate RT (90Gy/second, FLASH) has comparable tumor control to CONV with decreased toxicity, however, evaluation of immune response is limited. Using an orthotopic syngeneic model of brainstem DMG, we performed single-cell RNA sequencing (scRNA-seq) on CD45+ immune cells isolated from tumors four days post 15Gy FLASH or CONV RT, and compared to unirradiated tumor. We performed flow cytometry at day 4 and day 10 post-RT. ScRNA-seq reveals 33,308 immune cells in 17 unique clusters. Microglia (MG) make up 73.8% and non-resident myeloid cells make up 7.9% of cells and include macrophages (MAC), dendritic cells (DC) and Monocytes (MONO). Flow at day 4 and day 10 show no significant difference in proportion of immune cell subtypes comparing FLASH, CONV and tumor. With differential gene expression, FLASH and CONV provoke a similar inflammatory and IFN1 response in MG while in MACs and DCs IFN1 pathway expression is increased in CONV compared to FLASH (p&amp;lt; 0.001 for both), confirmed by flow at day 4 using IFNAR1 expression (MACs p&amp;lt; 0.05, DCs p&amp;lt; 0.01). Flow at day 10 post-RT shows increased IFNAR1 expression in MACs in both CONV and FLASH compared to tumor (p&amp;lt; 0.0001) while day 10 IFNAR1 in DCs is similar in all three groups. In summary, while immune proportions are similar comparing different dose rates of RT, IFN1 is differentially expressed in CONV compared to FLASH at day 4 in MACs and DCs, while this response at day 10 is similar comparing dose rates.
NCOG-32. THE SPECIFIC PSYCHOSOCIAL BURDEN OF CAREGIVERS OF ADULT NEURO-ONCOLOGICAL PATIENTS - A PROSPECTIVE STUDY
Authors: Mareike Spieker, Marion Rapp, Simone Goebel, André Karger, David Rieger, Lucia Grosse, Paula Bombach, Sylvia Kurz, Melina Hippler, Marcos Tatagiba, Michael Sabel, Ghazaleh Tabatabai, Mirjam Renovanz
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE The diagnosis of a brain tumor represents high burden for the patients’ caregivers (CG). Psychosocial screening tools adapted to the burden profile of CG are urgently required but do not exist. The aim was to develop a problem list for neuro-oncological CGs’ unmet needs for an application in combination to the Distress Thermometer scale. METHODS CG were prospectively assessed regarding changes in everyday life, relationship, social life, emotional, physical problems, and support needs, either via questionnaire (Center A) or by a qualitative interview (center B). A qualitative content analysis was performed by an inductive/deductive approach using MAXQDA® software. RESULTS A total of 50 caregivers were assessed (25 in center A via questionnaire, 25 in center B via interviews) during outpatient visits. Most frequently reported need was the need for psychological support (29/50, 58%). This was true after initial diagnosis (26/50, 52%) as well as in case of clinical deterioration of their loved-one (30/50, 60%). The results leaded to problem categories, congruent to the NCCN distress thermometer categories for cancer patients (practical, social, emotional, physical, and spiritual/existential problems). We detected new topics including “constraints/organization of (medical) appointments” (25/50, 50%) or “constant availability required for partner” (21/50, 42%). Also, 70% (35/50) put their own interests last or adapted their leisure activities. In the qualitative interviews (Center B), further items were identified, e.g., “dealing with psychological problems of the patient” (3/25, 12%), “different coping strategies among patient/caregiver” (4/25, 16%). We defined additional problem categories specifically adapted to CG of neurooncological patients, e.g., “problems due to neurocognitive/neuropsychological symptoms of the loved-one” and “problems with role as a caregiver”. CONCLUSION The interviews reflected the unmet needs of brain tumor caregivers. Our problem list developed for CG of neurooncological patients might allow for the targeted assessment and optimization of care.